Biomedical subjects

Donald Newgreen

Publications and source records attributed to Donald Newgreen.

6 recordsLinked to original sources

PubMed2006

The association between T-type Ca2+ current and outward current in isolated human detrusor cells from stable and overactive bladders.

OBJECTIVE: To determine if bladder overactivity in humans is associated with an altered activity of Ca(2+) channels in detrusor smooth muscle and the consequent activation of other ion channels. MATERIAL AND METHODS: Samples of bladder were obtained from patients with urodynamically stable bladders, or with idiopathic detrusor overactivity. Isolated cells were patch-clamped with pipettes containing a Cs(+)-based filling solution to isolate inward currents, or a K(+)-filling solution to measure outward current. Components of inward current were separated according to their sensitivity to NiCl(2) (< or =100 microm) and nifedipine. RESULTS: Ni(2+)-sensitive (T-type) and nifedipine-sensitive (L-type) current was recorded in all cells. The voltage- and time-dependent properties were similar in cells from both patient groups. However, the current density of the L-type current was less, and that of the T-type current was greater, in myocytes from overactive bladders. In cells from overactive bladders, the mean K(+) current over the range - 80 to - 50 mV was also higher than in control cells. This current was sensitive to the large-conductance channel modulator iberiotoxin and to NiCl(2) (100 microm) CONCLUSIONS: Detrusor myocytes from overactive human bladders have a higher T-type Ca(2+) current density; we propose that this increases transient outward currents, and so might contribute to higher levels of spontaneous activity.

Action Potentials↗

PubMed2004

Mechanism-based pharmacokinetic-pharmacodynamic modeling of 5-HT1A receptor agonists: estimation of in vivo affinity and intrinsic efficacy on body temperature in rats.

The pharmacokinetic-pharmacodynamic (PK-PD) correlations of seven prototypical 5-HT(1A) agonists were analyzed on the basis of a recently proposed semi-mechanistic PK-PD model for the effect on body temperature. The resulting concentration-effect relationships were subsequently analyzed on the basis of the operational model of agonism to estimate the operational affinity (pK(A)) and efficacy (log tau) at the 5-HT(1A) receptor in vivo. The values obtained in this manner were compared with estimates of the affinity (pK(i)) and intrinsic efficacy (log[agonist ratio]) in a receptor-binding assay. Between 5-HT(1A) agonists wide differences in in vivo affinity and efficacy were observed, with values of the pK(A) ranging from 5.67 for flesinoxan to 8.63 for WAY-100,635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridinyl-cyclohexanecarboxamide] and of the log tau ranging from -1.27 for WAY-100,135 [N-(1,1-dimethylethyl)-4-(2-methoxyphenyl)-alpha-phenyl-1-piperazine-propanamide] to 0.62 for R-(+)-8-hydroxy-2-[di-n-propylamino)tetralin. Poor correlations were observed between the in vivo receptor affinity (pK(A)) and the affinity estimates in the in vitro receptor binding assay (pK(i); r(2) = 0.55, P > 0.05), which could in part be explained by differences in blood-brain distribution. In contrast, a highly significant correlation was observed between the efficacy parameters in vivo (log tau) and in vitro (log [agonist ratio]; r(2) = 0.76, P < 0.05). Thus by combining the previously proposed semi-mechanistic PK-PD model for the effect on body temperature with the operational model of agonism, a full mechanistic PK-PD model for 5-HT(1A) receptor agonists has been obtained, which is highly predictive of the in vivo intrinsic efficacy.

Animals↗

PubMed2004

Detrusor responses to prostaglandin E2 and bladder outlet obstruction in wild-type and Ep1 receptor knockout mice.

PURPOSE: Prostaglandins (PGs) are suggested to be involved in the pathophysiology of different bladder disorders and it has been demonstrated that cyclooxygenase-2 expression is increased as a consequence of bladder outflow obstruction. We investigated whether the PGE2 receptor EP1 is involved in the regulation of normal micturition, the response to intravesical PGE2 administration, and the development of bladder hypertrophy and overactivity due to bladder outlet obstruction (BOO). MATERIALS AND METHODS: Moderate BOO was created in EP1 receptor knockout (EP1KO) mice and their WT counterparts. After 1 week cystometry was performed in conscious animals before and after PGE2 instillation. Findings were compared to those in unobstructed control animals. Bladder wet weight was measured to document the degree of hypertrophy after BOO. RESULTS: There was no difference between unobstructed EP1KO and WT mice in urodynamic parameters but EP1KO mice did not respond to intravesical PGE2 instillation, while WT mice showed detrusor overactivity. The lack of EP1 receptor did not prevent bladder hypertrophy due to BOO. After BOO WT mice had pronounced detrusor overactivity, while this was negligible in EP1KO mice. CONCLUSIONS: The EP1 receptor appears not to be essential for normal micturition or the mediation of bladder hypertrophy due to BOO but it seems to have a role in the development of detrusor overactivity caused by PGE2 and outlet obstruction.

Animals↗

PubMed2003

Bladder overactivity in mice after 1 week of outlet obstruction. Mainly afferent dysfunction?

PURPOSE: Partial bladder outlet obstruction (BOO) is an established way to create bladder overactivity in animals. However, the micturition pattern achieved can vary considerably. We investigated the correlation between different micturition patterns, post-void residual urine, bladder capacity, bladder weight and in vitro contractility in a conscious mouse model of BOO. MATERIALS AND METHODS: Female MNRI mice with moderate (urethral) outlet obstruction were used. After 7 days of BOO cystometry without anesthesia was performed with the animal in a metabolic cage. Results were compared with those in unoperated controls and sham operated animals. In vitro contractility studies were performed. RESULTS: The majority of obstructed animals had an overactive voiding pattern with increased nonvoiding detrusor activity and without increased bladder weight. The remaining obstructed animals had significantly increased bladder weight and normal micturition volume but increased threshold pressure, bladder capacity and post-void residual urine. Subtle in vitro differences were found among the groups. CONCLUSIONS: The urodynamic characteristics of BOO mice correlate with bladder weight. However, detrusor overactivity in obstructed mice may develop without an increase in bladder weight and with only subtle changes in smooth muscle function, as investigated in vitro. This observation suggests that major disturbances caused by BOO may lie in the afferent arm of the signaling pathway.

Animals↗

PubMed2002

Enteric nervous system: development and developmental disturbances--part 2.

This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. Accurate descriptions of the phenotype of ENS dysplasias, and knowledge of genes which, when mutated, give rise to the disorders (see Part 1 in the previous issue of this journal), are not sufficient to give a real understanding of how these abnormalities arise. The often indirect link between genotype and phenotype must be sought in the early embryonic development of the ENS. Therefore, in this, the second part, we provide a description of the development of the ENS, concentrating mainly on the origin of the ENS precursor cells and on the cell migration by which they become distributed throughout the gastrointestinal tract. This section also includes experimental evidence on the controls of ENS formation derived from classic embryological, cell culture, and molecular genetic approaches. In addition, for reasons of completeness, we also briefly describe the origins of the interstitial cells of Cajal, a cell population closely related anatomically and functionally to the ENS. Finally, a brief sketch is presented of current notions on the developmental processes between the genes and the morphogenesis of the ENS, and of the means by which the known genetic abnormalities might result in the ENS phenotype observed in Hirschsprung's disease.

Abnormalities, Multiple↗

PubMedDate not supplied

Enteric nervous system: development and developmental disturbances--part 1.

This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. In the first part, we describe the critical features of two principal abnormalities of ENS development: Hirschsprung's disease (HSCR) and intestinal neuronal dysplasia type B (INDB) in humans, and the similar abnormalities in animals. These represent the extremes of the diagnostic spectrum: HSCR has agreed and unequivocal diagnostic criteria, whereas the diagnosis and even existence of INDB as a clinical entity is highly controversial. The difficulties in diagnosis and treatment of both these conditions are discussed. We then review the genes now known which, when mutated or deleted, may cause defects of ENS development. Many of these genetic abnormalities in animal models give a phenotype similar or identical to HSCR, and were discovered by studies of humans and of mouse mutants with similar defects. The most important of these genes are those coding for molecules in the GDNF intercellular signaling system, and those coding for molecules in the ET-3 signaling system. However, a range of other genes for different signaling systems and for transcription factors also disturb ENS formation when they are deleted or mutated. In addition, a large proportion of HSCR cases have not been ascribed to the currently known genes, suggesting that additional genes for ENS development await discovery.

Abnormalities, Multiple↗